All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.
Cardiovascular diseases are well-recognised as the leading cause of death in the western world. These conditions include atherosclerosis, diabetes, hypertension, peripheral vascular disease, coronary artery disease, myocardial infarction, congestive heart failure, and cerebrovascular disease. Some of these conditions, in particular atherosclerosis and Type II diabetes, have been associated with lifestyle factors such as diet and lack of physical exercise. Cardiovascular conditions are one of the most common sequelae of both Type I and Type II diabetes. However, while lifestyle changes can significantly reduce the risk of cardiovascular diseases or can slow their development, not all patients are able to comply with strict dietary and/or exercise regimens. Moreover, some patients have a genetic predisposition to development of cardiovascular conditions. Consequently there is a great need in the art for pharmaceutical agents which can influence the underlying pathological mechanisms of development of these conditions, and/or relieve their symptoms.
For example, a wide variety of drugs is available for treatment of hypertension, and many of these are also used in the treatment of congestive heart disease and heart failure. However, few agents have been specifically developed for the treatment of heart failure alone.
It is estimated that chronic or congestive heart failure affects approximately 5,000,000 people in the United States alone, ie. approximately 2% of the population, with approximately 400,000 new cases being diagnosed each year. Hospital and out-patient management costs are responsible for approximately 2.5% of the total health care costs, and congestive heart failure is one of the single most common causes of death in industrialised societies. Current treatments for congestive heart failure are very poor, and no satisfactory agents are available. Thus currently the primary aim of treatment is to prevent progression of the condition. However, in most cases patients have to utilise multiple pharmaceutical agents, and if the condition is not controlled the only treatments available are heart transplant or external cardiac assists. Although heart transplantation can be very successful, only very few patients can be treated because of the acute shortage of donors and the requirement for histocompatibility. External cardiac assists are suitable only for short-term use.
One of the major processes associated with the development of cardiovascular diseases is a disturbance of the functional properties of the endothelium, ie. the lining layer of blood vessels. The vascular endothelium plays a pivotal role in regulating blood flow by releasing, at the appropriate time, a chemical called nitric oxide. This process is illustrated schematically in FIG. 1. Nitric oxide (NO) is a small molecule which diffuses readily and plays a major role in vascular relaxation.
NO is generated by a family of cellular enzymes, nitric oxide synthases (NOS), which make use of the amino acid L-arginine. All isoforms of NOS catalyze a five-electron oxidation of one of two guanidino nitrogen atoms in L-arginine to yield nitric oxide and L-citrulline, as shown in FIG. 1.
The reaction involves two monooxygenation reactions, with N-γ-hydroxy-L-arginine as an intermediate product. The reaction requires several redox cofactors, including reduced nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin adenine mononucleotide (FMN) and tetrahydrobiopterin (THB4). It is known that the rate of production of NO is largely dependent upon the supply of L-arginine, and that supplementation with larger doses of L-arginine, per se, can improve endothelial function.
The clinical features of congestive heart failure (CHF) result from a complex interaction between reduced ventricular function, neurohormonal activation, and impaired endothelial function. While endothelial dysfunction has been well documented, the mechanisms which contribute to this dysfunction remained unclear until very recently. Possible such mechanisms included reduced expression of muscarinic cholinergic receptors (M) on endothelial cells, altered intracellular signalling, reduced NO production, increased NO degradation, or an attenuated response by the intracellular targets of NO or cyclic GMP (cGMP). Supplementation with oral or intravenous L-arginine has been shown to improve endothelial function in some conditions which are characterised by endothelial dysfunction, most notably atherosclerosis (Lerman et al 1998; Creager et al., 1992; Girerd et al., 1990). Such supplements have been shown to improve endothelial function in patients with heart failure (Hirooka et al., 1994; Rector et al, 1996), and we have shown that transport of L-arginine is impaired in patients with congestive heart failure; this could lead to a relative deficiency of intracellular arginine, thereby reducing NO synthesis (Kaye et al., 2000).
While in principle supplementation with L-arginine will have a beneficial effect, this approach suffers from the serious disadvantage that the doses required are extremely high, leading to toxic side effects as a result of the concomitant increase in urea levels. Thus there is a need in the art for alternative agents which are able to modulate L-arginine transport, without adversely affecting circulating urea levels. While supplementation with L-arginine does improve vasodilation, the doses of L-arginine which are required are very large, and result in potentially dangerous increases in blood urea levels. Thus an alternative method is needed.
Lowering intracellular L-arginine levels by inhibiting L-arginine transport has potential in the treatment of conditions in which the L-arginine-nitric oxide pathway is excessively active. These include sepsis resulting from infection, in which the NO pathway, particularly the pathway involving the inducible form of NOS (iNOS), or possibly L-arginine transport, is overactive; inflammation caused by non-infective disease states, including but not limited to arthritis, and chronic liver disease with its attendant toxaemia.